Preparation of sufentanil citrate and sufentanil base

ABSTRACT

Provided herein are processes for forming sufentanil citrate from sufentanil base. One process comprises forming sufentanil citrate in the presence of a polar non-aqueous solvent. Other processes comprise forming sufentanil citrate in the presence of water.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the priority of U.S. Provisional ApplicationSer. No. 62/166,911, filed May 27, 2015, the disclosure of which isincorporated herein in its entirety.

FIELD OF THE INVENTION

The present invention generally relates to the preparation of sufentanilsalts and free base.

BACKGROUND OF THE INVENTION

Sufentanil is a member of the series of potent fentanyl analogs. It hasa high selectivity and affinity (approximately 10 times greater thanfentanyl) for “mu” opiate receptors. When compared with fentanyl,sufentanil's pharmacokinetic profile shows a smaller volume ofdistribution, resulting in a terminal half-life intermediate betweenalfentanil and fentanyl. Additionally, sufentanil, like fentanyl, doesnot cause histamine release. The chemical name for sufentanil isN-[4-(methoxymethyl)-1-[2-(2-thienypethyl]-4-piperidinyl]-N-phenylpropanamide.In its citrate form, the chemical name isN-[4-(methoxymethyl)-1-[2-(2-thienypethyl]-4-piperidinyl]-N-phenylpropanamide,2-hydroxy-1,2,3-propanetricarboxylate.

The classical approach for preparing sufentanil citrate involves formingthe salt from sufentanil base with citric acid (using an approximate 1:1ratio) in water with charging everything upfront. Unfortunately, thisapproach leads to the salt oiling out of solution and latercrystallizing. This prior process also presents several other problems.First, considerable manual intervention is required to remove theaggregated product from the sidewalls of the reactor after the oiled-outproduct crystallizes. The uncontrolled crystallization causes theproduct to solidify into chunks that must be sieved or milled to obtainto a powder fine enough for pharmaceutical formulation. Milling of sucha potent compound also is extremely hazardous and raises exposureissues. Furthermore, a polishing sterile filtration is not possiblesince the reaction does not go through a homogeneous phase. Single stepreprocessing is also not possible (e.g., the material does notredissolve in the matrix). If the sufentanil citrate product failsspecifications (e.g., assay, HPLC, particulate matter, etc.), the saltmust be returned to the base form and the citrate crystallizationprocess must be repeated from the beginning. A need therefore exists foran improved salt formation and isolation method to address the latterproblems.

SUMMARY OF THE INVENTION

Briefly, therefore, one aspect of the present disclosure encompasses aprocess for forming sufentanil citrate from sufentanil base in thepresence of a polar non-aqueous solvent. The process comprises (a)contacting sufentanil base with a polar non-aqueous solvent to form amixture, where the volume to mass ratio of the polar non-aqueous solventto sufentanil base is from about 2:1 to about 12:1, and (b) contactingthe mixture with citric acid to form a sufentanil citrate mixture,wherein the sufentanil citrate mixture is free of an oil phase.

Another aspect of this disclosure provides a process for formingsufentanil citrate from sufentanil base in the presence of water. Theprocess comprises (a) forming a mixture of citric acid and water inwhich the volume to mass ratio of water to citric acid is from about 2:1to about 12:1, and (b) adding sufentanil base to the mixture to formsufentanil citrate, wherein the mole to mole ratio of citric acid tosufentanil base is from about 2:1 to about 5.

A further aspect of this disclosure provides a process for formingsufentanil base from sufentanil citrate. The process comprises (a)contacting sufentanil citrate with at least one polar solvent to form amixture, (b) contacting the mixture with a proton acceptor to form asufentanil base mixture, (c) cooling the sufentanil base mixture to formsolid sufentanil base, and (d) recovering the solid sufentanil base.

Other features and iterations of the invention are described in moredetail below.

DETAILED DESCRIPTION OF THE INVENTION

Manufacturing sufentanil citrate is uniquely difficult compared to othersufentanil analogs in particular, as well as other activepharmaceuticals in general, because of sufentanil citrate's unusual andpronounced tendency to exit initially from the mother liquor as an oilprior to crystallization. The oily product initially coats the bottomand sides of the reaction vessel, agitator, and agitator shaft, and thensolidifies as a glass within hours. The solidified product must then bemanually removed, exposing the manufacturing operators to a hazardouspotent compound for several hours every time this process is run.Scraping of the walls of a reactor is also undesirable. In the jargon ofthe development chemist, any process where an oil is formed or theproduct sticks to the reactor or other equipment is deemed “unscalable,”because the process cannot be run using standard manufacturingoperations and equipment—for example pumps, impellers, centrifuges, andfilters—as opposed to a laboratory setting where material may becollected and moved by hand under visual observation.

Disclosed herein are processes for preparing sufentanil citrate whichovercome the latter limitations; providing a scalable and robust processfor producing sufentanil citrate without the need for intensive manualintervention. The present disclosure encompasses a process for formingsufentanil citrate from sufentanil base, and for recovering sufentanilbase from the mother liquor. Applying the methods described herein, thecrystallized sufentanil citrate product remains well-suspended in themother liquor and does not aggregate, as is the problem with sufentanilcitrate prepared with previous methods. The processes disclosed hereinproceeds through a homogeneous solution phase, is reversible; compatiblewith a polishing filtration and with single step reprocessing. As aresult, yield and process capabilities are improved.

(I) Process for Preparing Sufentanil Citrate from Sufentanil Base in aPolar Non-Aqueous Solvent

One aspect of the disclosure encompasses a process for formingsufentanil citrate from sufentanil base in the presence of a polarnon-aqueous solvent. The process comprises (a) contacting sufentanilbase with a polar non-aqueous solvent to form a mixture, wherein thevolume to mass ratio of the polar non-aqueous solvent to sufentanil baseis from about 2:1 to about 12:1. The mixture is then (b) contacted withcitric acid to form sufentanil citrate. In some embodiments, the processmay further comprise (c) cooling the mixture from above to form solidsufentanil citrate, and (d) recovering solid sufentanil citrate.

As used herein, the term “mixture” refers to homogeneous (in solution)or heterogeneous (suspended) matrix. In some embodiments, the mixturemay be a homogeneous or heterogeneous solution.

(a) Step A—Reaction Mixture

Step (a) of the process comprises contacting sufentanil base with apolar non-aqueous solvent to form a mixture. The process commences withthe formation of a reaction mixture comprising sufentanil base and apolar non-aqueous solvent at a volume to mass ratio of the polarnon-aqueous solvent to sufentanil base of from about 2:1 to about 12:1.

“Non-aqueous” solvent, as used herein, refers to solvents or solventsystems without an added water component but which are not necessarily“anhydrous” or “dry”; that is, trace amounts of water may accompany thesolvent, for example, as water absorbed from the atmosphere or waterderived from citric acid itself which can also exist as a monohydrate.The solvent may be a polar non-aqueous protic solvent or a polarnon-aqueous aprotic solvent. Non-limiting examples of suitable polarnon-aqueous protic solvents include alcohols such as methanol, ethanol,1-propanol, 2-propanol, isobutanol, 1-butanol, 2-butanol, sec-butanol,t-butanol, and the like; diols such as propylene glycol; amides such asformamide, acetamide, and the like; and combinations of any of theabove. Non-limiting examples of suitable polar non-aqueous aproticsolvents include acetone, acetonitrile, diethoxymethane,N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO),N,N-dimethylpropanamide (or dimethylpropionamide; DMP),1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),1,3-dimethyl-2-imidazolidinone (DMI), 1,2-dimethoxyethane (DME),dimethoxymethane, bis(2-methoxyethyl)ether, N,N-dimethylacetamide (DMA),N-methyl-2-pyrrolidinone (NMP), 1,4-dioxane, ethyl formate, formamide,hexachloroacetone, hexamethylphosphoramide, methyl acetate,N-methylacetamide, N-methylformamide, methylene chloride, methoxyethane,morpholine, nitrobenzene, nitromethane, propionitrile, pyridine,sulfolane, tetramethylurea, tetrahydrofuran (THF), 2-methyltetrahydrofuran, tetrahydropyran (THF), trichloromethane, andcombinations thereof. Specific polar non-aqueous solvents that may beemployed include, for example, ethyl acetate, isopropyl acetate, methylisobutyl ketone, methyl ethyl ketone, and C₁-C₅ alcohol, such asmethanol, ethanol, 1-propanol, 2-propanol (isopropyl alcohol, IPA),1-butanol, 2-butanol, sec-butanol, and tert-butanol, and combinationsthereof.

In particular embodiments, the polar non-aqueous solvent may be a U.S.Food and Drug Administration (FDA) Class 3 approved solvent. The FDAdefines Class 3 solvents as including no solvent known as a human healthhazard at levels normally accepted in pharmaceuticals. Available dataindicate that Class 3 solvents are less toxic than other solvents inacute or short-term studies and are negative in genotoxicity studies.The FDA considers amounts of these residual solvents of 50 mg per day orless (corresponding to 5,000 ppm or 0.5 percent) as acceptable withoutjustification. Higher amounts may also be acceptable provided they arerealistic in relation to manufacturing capability and good manufacturingpractice (GMP). Examples of suitable polar non-aqueous FDA Class 3solvents include, but are not limited to, acetic acid, acetone, anisole,2-butanol, butyl acetate, tert-butylmethyl ether, DMSO, ethanol, ethylacetate, ethyl ether, ethyl formate, formic acid, isobutyl acetate,isopropyl acetate, methyl acetate, 3-methyl-1-butanol, methylethylketone (MEK), methylisobutyl ketone (MIBK), 2-methyl-1-propanol,1-pentanol, 1-propanol, 2-propanol, propyl acetate, and tetrahydrofuran(THF). In exemplary embodiments, the solvent may be ethyl acetate,isopropyl acetate, MEK, MIBK, 1-butanol, 2-butanol, ethanol, 1-propanol,2-propanol (isopropyl alcohol, IPA), or 2-methyl-1-propanol(isobutanol).

In general, the volume to mass ratio of the solvent to sufentanil baseranges from about 2:1 to about 12:1. In various embodiments, the volumeto mass ratio of the solvent to sufentanil base may range from about 2:1to about 12:1, from about 2.5:1 to about 10:1, from about 3:1 to about8:1, or from about 3.5:1 to about 6:1. In exemplary embodiments, thevolume to mass ratio of the solvent to sufentanil base may be from about4:1 to about 5:1.

(b) Step A—Reaction Conditions

In general, contact between the polar non-aqueous solvent and sufentanilbase is conducted at a temperature that ranges from about 20° C. toabout 90° C. In various embodiments, the reaction may be conducted at atemperature from about 20° C. to about 30° C., from about 30° C. toabout 40° C., from about 40° C. to about 50° C., from about 50° C. toabout 60° C., from about 60° C. to about 70° C., from about 70° C. toabout 80° C., or from about 80° C. to about 90° C. In exemplaryembodiments, the reaction may be conducted at a temperature of about 50°C. In other exemplary embodiments, the contacting may be conducted at atemperature from about 60° C. to about 80° C., for example at about 70°C. The contacting may be conducted in an inert atmosphere (e.g., undernitrogen or argon) and under ambient pressure. Contact between the polarnon-aqueous solvent and sufentanil base may be facilitated by stirring,mixing, shaking, or any other means known in the art.

Typically, the contacting step is allowed to proceed for a sufficientperiod of time until the sufentanil base is incorporated into themixture. In some embodiments, the mixture may be a homogenous solution.Generally, the contacting may proceed from about 1 minute to about 60minutes. In some embodiments, the reaction may proceed from about 1minute to about 5 minutes, from about 5 minutes to about 10 minutes,from about 10 minutes to about 15 minutes, from about 15 minutes toabout 20 minutes, from about 20 minutes to about 25 minutes, from about25 minutes to about 30 minutes, from about 30 minutes to about 35minutes, from about 35 minutes to about 40 minutes, from about 40minutes to about 45 minutes, from about 45 minutes to about 50 minutes,from about 50 minutes to about 55 minutes, or from about 55 minutes toabout 60 minutes.

In some embodiments, the mixture may be filtered (polishing filtration)before proceeding to the next step. In particular, the mixture may befiltered at a temperature that ranges from about 20° C. to about 90° C.,as described above, in order to remove, for example, undissolvedsufentanil base or other impurities before proceeding to reaction withcitric acid.

(c) Step B—Reaction Mixture

Step (b) of the process further comprises contacting the mixture fromstep (a) with citric acid to form sufentanil citrate. The processcommences with the formation of a reaction mixture comprising themixture from step (a), which is detailed above, and citric acid, whichmay be added directly to the mixture from step (a) as a solid or asolution in a solvent.

The reaction mixture comprises citric acid. The citric acid may bepresent as the anhydrate, where the crystalline structure of the citricacid is not associated with any water molecules, or a hydrate, where thecrystalline structure of the citric acid is associated with one or morewater molecules. Examples of suitable hydrates include citric acidhemihydrate, citric acid monohydrate, citric acid sesquihydrate, citricacid dihydrate, and citric acid trihydrate.

In some embodiments, the citric acid may be dissolved in a solvent, asdefined above in section (I)(a) above. In exemplary embodiments, thesolvent may be ethyl acetate, isopropyl acetate, methyl isobutyl ketone,methyl ethyl ketone, or C₁-C₅ alcohol. In general, the volume to massratio of the solvent to the citric acid ranges from about 0.1:1 to about10:1. In various embodiments, the volume to mass ratio of the solvent tocitric acid may range from about 0.1:1 to about 10:1, from about 0.2:1to about 8:1, from about 0.3:1 to about 6:1, from about 0.4:1 to about4:1, or from about 0.5:1 to about 2:1. In exemplary embodiments, thevolume to mass ratio of the solvent to citric acid may be from about0.5:1 to about 2:1, or about 1:1.

The amount of citric acid added to the reaction mixture can and willvary. In general, the mole to mole ratio of citric acid to sufentanilbase may range from about 0.9:1 to about 1.5:1. In various embodiments,the mole to mole ratio of citric acid to sufentanil base may range fromabout 0.9:1 to about 1.5:1, from about 0.92:1 to about 1.4:1, from about0.94:1 to about 1.3:1, from about 0.96:1 to about 1.2:1, or from about0.98:1 to about 1.1:1. In exemplary embodiments, the mole to mole ratioof citric acid to sufentanil base may range from about 0.9:1 to about1.1:1.

(d) Step B—Reaction Conditions

The temperature at which contact between citric acid and the mixture of(a) is conducted can and will vary. In general, the contacting isconducted at a temperature that ranges from about 20° C. to about 90° C.In various embodiments, the contacting may be conducted at a temperaturefrom about 20° C. to about 30° C., from about 30° C. to about 40° C.,from about 40° C. to about 50° C., from about 50° C. to about 60° C.,from about 60° C. to about 70° C., from about 70° C. to about 80° C., orfrom about 80° C. to about 90° C. In an exemplary embodiment, thecontacting may be conducted at a temperature of about 80° C. In otherexemplary embodiments, the contacting may be conducted at a temperaturefrom about 60° C. to about 75° C., for example at about 70° C. Thecontacting may be conducted in an inert atmosphere (e.g., under nitrogenor argon) and under ambient pressure. Contact between citric acid andsufentanil base in the mixture of (a) may be facilitated by stirring,mixing, shaking, or any other means known in the art. In variousembodiments, the mixture of step (b) may be substantially or completelyfree of an oil phase comprising a sufentanil species. In particular, inembodiments in which the polar non-aqueous solvent is 2-propanol, themixture of (b) is devoid of an oil phase.

Typically, the reaction is allowed to proceed for a sufficient period oftime until the reaction is complete, as determined by any of numerousmethods known in the art. In this context, a “completed reaction”generally means that the reaction mixture contains a significantlydiminished amount of sufentanil base, and a significantly increasedamount of sufentanil citrate compared to the amounts of each present atthe beginning of the reaction. In a completed reaction, the amount ofsufentanil base remaining in the reaction mixture may be less than about3%, or less than about 1%. In general, the reaction may proceed forabout 0.5 hours to about 24 hours. In some embodiments, the reaction mayproceed from about 0.5 hours to about 1 hour, from about 1 hour to about3 hours, from about 3 hours to about 4 hours, from about 4 hours toabout 6 hours, from about 6 hours to about 8 hours, from about 8 hoursto about 12 hours, from about 12 hours to about 18 hours, or from about18 hours to about 24 hours.

In embodiments where the citric acid is dissolved in solvent beforeaddition to the mixture of step (a), the citric acid solution may beadded over a period of about 1 minute to about 60 minutes. In someembodiments, the citric acid solution may be added over a period ofabout 1 minute to about 5 minutes, of about 5 minutes to about 10minutes, of about 10 minutes to about 15 minutes, of about 15 minutes toabout 20 minutes, of about 20 minutes to about 25 minutes, of about 25minutes to about 30 minutes, of about 30 minutes to about 35 minutes, ofabout 35 minutes to about 40 minutes, of about 40 minutes to about 45minutes, of about 45 minutes to about 50 minutes, of about 50 minutes toabout 55 minutes, or of about 55 minutes to about 60 minutes. In aparticular embodiment, the citric acid solution may be added over aperiod of about 50 minutes.

In some embodiments, the mixture may be filtered (polishing filtration)before proceeding to the next step. In particular, the mixture may befiltered at a temperature that ranges from about 20° C. to about 90° C.,as described above.

The sufentanil citrate in the mixture may be isolated from the mixtureusing techniques known to those of skill in the art. Non-limitingexamples of suitable techniques include precipitation, extraction,evaporation, distillation, chromatography, and crystallization. Inexemplary embodiments, the sufentanil citrate may be isolated accordingto the methods described in the sections (I)(e)-(f) below. Thesufentanil citrate may be used as is, or may be converted to anothercompound using techniques familiar to those of skill in the art.

The yield of sufentanil citrate can and will vary. Typically, the yieldof sufentanil citrate may be at least about 35%. In one embodiment, theyield of sufentanil citrate may range from about 35% to about 65%. Inanother embodiment, the yield of sufentanil citrate may range from about65% to about 75%. In yet another embodiment, the yield of sufentanilcitrate may range from about 75% to about 85%. In a further embodiment,the yield of the sufentanil citrate may range from about 85% to about95%. In still another embodiment, the yield of the sufentanil citratemay be greater than about 95%. In still a further embodiment, the yieldof the sufentanil citrate may be greater than about 99%.

(e) Step C

In some embodiments, the process may further comprise step (c) whichcomprises cooling the mixture from step (b) to form solid sufentanilcitrate. Generally, the reaction mixture of step (c) is the same as thereaction mixture of step (b), but in some embodiments, the reactionmixture of step (b) may be seeded with crystals of sufentanil citrate.For example, in embodiments in which the polar non-aqueous solvent is2-propanol, seed crystals of sufentanil citrate may be added to themixture of step (b). In general, the mole to mole ratio of sufentanilcitrate seed crystals to sufentanil citrate in the mixture may rangefrom about 0.0001:1 to about 0.05:1. In various embodiments, the mole tomole ratio of sufentanil citrate seed crystals to sufentanil citrate inthe mixture may range from about 0.0001:1 to about 0.0005:1, from about0.0005:1 to about 0.001:1, from about 0.001:1 to about 0.005:1, fromabout 0.005:1 to about 0.01:1, or from about 0.01:1 to about 0.05:1. Inan exemplary embodiment, the mole to mole ratio of sufentanil citrateseed crystals to sufentanil citrate in the mixture may range from about0.001:1 to about 0.05:1.

The temperature to which the reaction mixture of step (b) may be seededcan and will vary. In general, the temperature will range from 30° C. toabout 70° C. In various embodiments, the temperature may range fromabout 30° C. to about −40° C., from about 40° C. to about 50° C., fromabout 50° C. to about 60° C., or from about 60° C. to about 70° C. Inpreferred embodiments, the temperature range in which the reaction maybe seeded may be about 60° C.

The temperature to which the mixture of (b) is cooled can and will vary.In general, the temperature will range from about −20° C. to about 70°C. In various embodiments, the temperature may range from about −20° C.to about −10° C., from about −10° C. to about 0° C., from about 0° C. toabout 5° C., from about 5° C. to about 10° C., from about 10° C. toabout 20° C., from about 20° C. to about 30° C., from about 30° C. toabout 40° C., from about 40° C. to about 50° C., from about 50° C. toabout 60° C., or from about 60° C. to about 70° C. In some embodiments,the temperature of the reaction is cooled may range from about −5° C. toabout 5° C. In a preferred embodiment, the temperature of the cooledreaction may be about 50° C.

Typically, the reaction is allowed to proceed for a sufficient period oftime until the reaction is complete, as detailed above. For example, thecooling step may proceed until no further (visibly detectable or bylaser methods) solid sufentanil citrate is formed. In general, thereaction may proceed for about 0.5 hours to about 24 hours. In someembodiments, the reaction may proceed from about 0.5 hours to about 1hour, from about 1 hour to about 3 hours, from about 3 hours to about 4hours, from about 4 hours to about 6 hours, from about 6 hours to about8 hours, from about 8 hours to about 12 hours, from about 12 hours toabout 18 hours, or from about 18 hours to about 24 hours.

(f) Step D

In some embodiments, the process may further comprise step (d) whichcomprises recovering the solid sufentanil citrate from the mixture ofstep (c). In particular, the solid sufentanil citrate may be recoveredfrom the mixture of step (c) through filtration, for example throughvacuum filtration. The temperature at which the recovering step isconducted can and will vary. In general, the temperature will range fromabout −20° C. to about 60° C. In various embodiments, the temperaturemay range from about −20° C. to about −10° C., from about −10° C. toabout 0° C., from about 0° C. to about 5° C., from about 5° C. to about10° C., from about 10° C. to about 20° C., from about 20° C. to about30° C., from about 30° C. to about 40° C., from about 40° C. to about50° C., or from about 50° C. to about 60° C. In an exemplary embodiment,the temperature of the recovering step may be about 50° C.

The yield of solid sufentanil citrate can and will vary. Typically, theyield of solid sufentanil citrate may be at least about 35%. In oneembodiment, the yield of solid sufentanil citrate may range from about35% to about 65%. In another embodiment, the yield of solid sufentanilcitrate may range from about 65% to about 75%. In yet anotherembodiment, the yield of solid sufentanil citrate may range from about75% to about 85%. In a further embodiment, the yield of the solidsufentanil citrate may range from about 85% to about 95%. In stillanother embodiment, the yield of the solid sufentanil citrate may begreater than about 95%. In further embodiments, the yield of sufentanilcitrate may be greater than about 99%. In an exemplary embodiment, thesolid sufentanil citrate recovered at step (d) may have a yield of atleast about 85%.

The solid sufentanil citrate also may be further dried using any methodknown in the art to remove residual solvent. Suitable methods includevacuum filtration, oven drying, and reduction in vacuo, for example on arotary evaporator or attached to a high vacuum manifold. In furtherembodiments, the solid sufentanil citrate may be dried at elevatedtemperature, for example from about 35° C. to about 65° C.

In various embodiments, the solid sufentanil citrate recovered at step(d) may contain less than about 5000 ppm of solvent, for example, lessthan about 4500 ppm, less than about 4000 ppm, less than about 3500 ppm,less than about 3000 ppm, less than about 2500 ppm, less than about 2000ppm, less than about 1500 ppm, less than about 1000 ppm, less than about500 ppm, or less than about 100 ppm. In other embodiments, the solidsufentanil citrate recovered at step (d) may contain more than about5000 ppm of solvent. In a preferred embodiment, the solid sufentanilcitrate recovered in step (d) may contain less than 2000 ppm of solvent.

(g) Further processing

The mixture remaining from step (d) after the recovery of solidsufentanil citrate may be further processed according to section (III)below to provide recoverable solid sufentanil base.

(II) Processes for Preparing Sufentanil Citrate from Sufentanil Base inWater

Another aspect of the present disclosure provides processes for formingsufentanil citrate from sufentanil base in the presence of water. Ingeneral, the processes comprise (a) forming a mixture of citric acid andwater and (b) adding sufentanil base to the mixture to form sufentanilcitrate. The processes for forming sufentanil citrate in presence ofwater can be divided into two iterations of the general process.

The first water method comprises forming a mixture with a highconcentration of citric acid during the first step of the process (al),wherein the volume to mass ratio of water to citric acid is from about2:1 to about 12:1, and adding sufentanil base during the second step ofthe process (b1), wherein the mole to mole ratio of citric acid tosufentanil base in the mixture of (a1) ranges from about 2:1 to about5:1; and step (b1) generally is performed at a temperature of 85° C. orless. In some instances, this iteration may further comprise (c1)cooling the mixture from step (b1) to form solid sufentanil citrate, and(d1) recovering solid sufentanil citrate.

The second water method comprises forming two different mixtures ofsufentanil citrate, wherein one mixture is added to the other mixture.The first (high citric acid) mixture of sufentanil citrate is preparedby (a2) forming a first mixture of citric acid and water in which thevolume to mass ratio of water to citric acid is from about 2:1 to about12:1; and (b2) adding about 4% to about 35% of the total amount ofsufentanil base to the first mixture of citric acid and water, whereinmole to mole ratio of citric acid to sufentanil base ranges from about2:1 to about 5:1. The method further comprises (c2) cooling the firstmixture of sufentanil citrate. A second (low citric acid) mixture ofsufentanil citrate is prepared by (d2) forming a second mixture ofcitric acid and water in which the volume to mass ratio of water tocitric acid is from about 10:1 to about 22:1, and (e2) adding about 65%to about 96% of the total amount of sufentanil base to the secondmixture of citric acid and water, wherein the mole to mole ratio ofcitric acid to sufentanil base ranges from about 0.5:1 to about 2:1. Themethod further comprises (f2) adding the second (low citric acid)mixture of sufentanil citrate from step (e2) to the first (high citricacid) mixture of sufentanil citrate from step (c2); and (g2) cooling themixture from step (f2) to form solid sufentanil citrate. This method mayfurther comprise (h2) recovering the solid sufentanil citrate.

Each of these methods is presented in more detail below:

(a) Water Method 1

(i) Step A1

In the first iteration of the process for preparing sufentanil citratefrom sufentanil base in the presence of water, step (a1) comprisesforming a mixture of citric acid and water.

The citric acid may be present in any form described above in section(I)(c). In general, the volume to mass ratio of water to citric acid mayrange from about 2:1 to about 12:1. In various embodiments, the volumeto mass ratio of water to citric acid may range from about 2:1 to about12:1, from about 3:1 to about 11:1, from about 4:1 to about 10:1, fromabout 5:1 to about 9:1, or from about 6:1 to about 8:1, or from about6.5:1 to about 7.5:1. In some embodiments, the volume to mass ratio ofwater to citric acid may be about 7:1.

The reaction between citric acid and water is conducted at a temperatureof about 100° C. or less. For example, the temperature may range fromabout 20° C. to about 40° C., from about 40° C. to about 60° C., fromabout 60° C. to about 80° C., or from about 80° C. to about 100° C. Inexemplary embodiments, the temperature may range from about 20° C. toabout 30° C.

In general, citric acid is added in one portion. The contacting step isallowed to proceed for a sufficient period of time until the citric acidis incorporated into the mixture. In some embodiments, the mixture maybe a homogenous solution. Generally, the contacting may proceed fromabout 1 minute to about 60 minutes. In some embodiments, the reactionmay proceed from about 1 minute to about 5 minutes, from about 5 minutesto about 10 minutes, from about 10 minutes to about 15 minutes, fromabout 15 minutes to about 20 minutes, from about 20 minutes to about 25minutes, from about 25 minutes to about 30 minutes, from about 30minutes to about 35 minutes, from about 35 minutes to about 40 minutes,from about 40 minutes to about 45 minutes, from about 45 minutes toabout 50 minutes, from about 50 minutes to about 55 minutes, or fromabout 55 minutes to about 60 minutes. Contact between citric acid andwater may be facilitated by stirring, mixing, shaking, or any othermeans known in the art.

The reaction may be conducted in an inert atmosphere (e.g., undernitrogen or argon) and under ambient pressure. In various embodiments,the mixture of (al) may be substantially or completely free ofundissolved species. In some embodiments, the mixture of (al) may befiltered (polishing filtration) to remove undissolved impurities beforeproceeding to the next step.

(ii) Step B1

Step (b1) of this iteration comprises adding sufentanil base to themixture of (a1).

In general, the mole to mole ratio of citric acid to sufentanil base mayrange from about 2:1 to about 5:1. In various embodiments, the moleratio of citric acid to sufentanil base may range from about 2.0:1 to5.0:1, from about 2.25:1 to 4.5:1, from about 2.5:1 to about 4.0:1, orfrom about 2.75:1 to about 3.5:1. In exemplary embodiments, the mole tomole ratio of citric acid to sufentanil base may range from about 2.0:1to about 3.0:1.

The reaction between the sufentanil base and citric acid mixturegenerally is conducted at a temperature of about 85° C. or less. Forexample, the temperature may range from about 20° C. to about 40° C.,from about 40° C. to about 60° C., from about 60° C. to about 70° C., orfrom about 70° C. to about 85° C. In exemplary embodiments, thetemperature may range from about 60° C. to about 85° C.

In general, sufentanil base is added on one portion. Contact betweensufentanil base and citric acid may proceed for about 0.5 hours to about24 hours. In some embodiments, the reaction may proceed from about 0.5hours to about 1 hour, from about 1 hour to about 3 hours, from about 3hours to about 4 hours, from about 4 hours to about 6 hours, from about6 hours to about 8 hours, from about 8 hours to about 12 hours, fromabout 12 hours to about 18 hours, or from about 18 hours to about 24hours. Contact between sufentanil base and citric acid may befacilitated by stirring, mixing, shaking, or any other means known inthe art.

The reaction may be conducted in an inert atmosphere (e.g., undernitrogen or argon) and under ambient pressure. In various embodiments,the mixture of (b1) may be substantially or completely free of an oilphase comprising a sufentanil species. In some embodiments, the mixtureof (b1) may be filtered to remove undissolved sufentanil base and/orother impurities before proceeding to the next step.

(iii) Step C1

In various instances, this iteration may further comprise (c1) coolingthe mixture from step (b1) to form solid sufentanil citrate, and (d1)recovering solid sufentanil citrate from the mixture of (c1).

In some instances, this iteration may further comprise (c1) cooling themixture from step (b1) to form solid sufentanil citrate. The temperatureto which the mixture of (b1) is cooled can and will vary. In general,the temperature may range from about −20° C. to about 60° C. In variousembodiments, the temperature may range from about 20° C. to about −10°C., from about −10° C. to about 0° C., from about 0° C. to about 5° C.,from about 5° C. to about 10° C., from about 10° C. to about 20° C.,from about 20° C. to about 30° C., from about 30° C. to about 40° C.,from about 40° C. to about 50° C., or from about 50° C. to about 60° C.In some embodiments, the temperature of the reaction may range fromabout 0° C. to about 5° C. In other embodiments, the temperature of thereaction may be less than about −5° C.

Typically, the reaction is allowed to proceed for a sufficient period oftime until the reaction is complete. For example, the cooling step mayproceed until no further (visibly detectable or by lasers) solidsufentanil citrate is formed. In general, the reaction may proceed forabout 0.5 hours to about 24 hours. In some embodiments, the reaction mayproceed from about 0.5 hours to about 1 hour, from about 1 hour to about3 hours, from about 3 hours to about 4 hours, from about 4 hours toabout 6 hours, from about 6 hours to about 8 hours, from about 8 hoursto about 12 hours, from about 12 hours to about 18 hours, or from about18 hours to about 24 hours.

(iv) Step D1

This iteration also may further comprise (d1) recovering the solidsufentanil citrate after step (c1). The solid sufentanil citrate may berecovered from the mixture of step (c1) through filtration, for examplethrough vacuum filtration. The temperature at which the recovering stepis conducted can and will vary. In general, the temperature may rangefrom about −20° C. to about 60° C. In various embodiments, thetemperature may range from about −20° C. to about −10° C., from about−10° C. to about 0° C., from about 0° C. to about 5° C., from about 5°C. to about 10° C., from about 10° C. to about 20° C., from about 20° C.to about 30° C., from about 30° C. to about 40° C., from about 40° C. toabout 50° C., or from about 50° C. to about 60° C. In exemplaryembodiments, the temperature of the recovering step may range from about0° C. to about 25° C.

The yield of solid sufentanil citrate can and will vary. Typically, theyield of solid sufentanil citrate may be at least about 35%. In oneembodiment, the yield of solid sufentanil citrate may range from about35% to about 65%. In another embodiment, the yield of solid sufentanilcitrate may range from about 65% to about 75%. In yet anotherembodiment, the yield of solid sufentanil citrate may range from about75% to about 85%. In a further embodiment, the yield of the solidsufentanil citrate may range from about 85% to about 95%. In stillanother embodiment, the yield of the solid sufentanil citrate may begreater than about 95%. In further embodiments, the yield of sufentanilcitrate may be greater than about 99%. In an exemplary embodiment, thesolid sufentanil citrate recovered at step (d1) may have a yield of atleast about 90%.

The solid sufentanil citrate also may be further dried using any methodknown in the art to remove water. Suitable methods include vacuumfiltration, oven drying, and reduction in vacuo, for example on a rotaryevaporator or attached to a high vacuum manifold. In furtherembodiments, the solid sufentanil citrate may be dried at elevatedtemperature, for example from about 35° C. to about 65° C.

The mixture remaining after the recovery of solid sufentanil citrate atstep (d1) may be further processed according to section (III) below toprovide solid sufentanil base.

(b) Water Method 2

The second iteration of the process for preparing sufentanil citratefrom sufentanil base in the presence of water comprises forming twodifferent mixtures of sufentanil citrate and then combining the twomixtures.

(i) Step A2

The first step of this iteration comprises forming a first mixture ofcitric acid and water, in which the concentration of citric acid ishigh. Forming the mixture of citric acid and water is essentiallyidentical to that described above in section (II)(a)(i).

In general, the volume to mass ratio of water to citric acid in the highcitric acid mixture may range from about 2:1 to about 12:1. In variousembodiments, the volume to mass ratio of water to citric acid in thehigh citric acid mixture may range from about 1:1 to about 9:1, fromabout 2:1 to about 8:1, from about 3:1 to about 7:1, or from about 4:1to about 6:1. In some embodiments, the volume to mass ratio of water tocitric acid in the high citric acid mixture may be about 5:1.

(ii) Step B2

The next step of this iteration comprises forming the first mixture ofsufentanil citrate (high citric acid) by adding about 4% to about 35% ofthe total amount of sufentanil base to the high citric acid mixture of(a2). In general, the mole to mole ratio of citric acid to sufentanilbase may range from about 2:1 to about 5:1. In various embodiments, themole ratio of citric acid to sufentanil base may range from about 2.0:1to 5.0:1, from about 2.25:1 to 4.5:1, from about 2.5:1 to about 4.0:1,or from about 2.75:1 to about 3.5:1. In exemplary embodiments, the moleto mole ratio of citric acid to sufentanil base may range from about2.0:1 to about 3.0:1. In various embodiments, the amount of sufentanilbase added to the first mixture of aqueous citric acid may range fromabout 4% to about 10%, from about 10% to about 15%, from about 15% toabout 20%, from about 20% to about 25%, from about 25% to about 30%, orfrom about 30% to about 35% total amount of sufentanil base. Inexemplary embodiments, the amount of sufentanil base added to the firstmixture of (a2) may be 10% to about 20%, or about 15%, of the totalamount of sufentanil base.

In general, step (b2) of the process is conducted at a temperature of90° C. or less. In various embodiments, the reaction may be conducted ata temperature from about 20° C. to about 40° C., from about 40° C. toabout 60° C., from about 60° C. to about 80° C., or from about 80° C. toabout 90° C. In exemplary embodiments, the temperature may range fromabout 70° C. to about 85° C.

Contact between sufentanil base and the high citric acid mixture at step(b2) may proceed for about 0.5 hours to about 24 hours. In someembodiments, the reaction may proceed from about 0.5 hours to about 1hour, from about 1 hour to about 3 hours, from about 3 hours to about 4hours, from about 4 hours to about 6 hours, from about 6 hours to about8 hours, from about 8 hours to about 12 hours, from about 12 hours toabout 18 hours, or from about 18 hours to about 24 hours. Contactbetween sufentanil base and high citric acid mixture may be facilitatedby stirring, mixing, shaking, or any other means known in the art.

The reaction may be conducted in an inert atmosphere (e.g., undernitrogen or argon) and under ambient pressure. In various embodiments,the mixture of (b2) may be substantially or completely free of an oilphase comprising a sufentanil species. In some embodiments, the mixtureof (b2) may be filtered (polishing filtration) to remove undissolvedsufentanil base and/or other impurities before proceeding to the nextstep.

(iii) Step C2

The third step of this iteration comprises cooling the first sufentanilcitrate mixture (high citric acid) of (b2). The cooling step may beconducted essentially as described above in section (II)(a)(iii).

(iv) Step D2

Step (d2) comprises forming a second mixture of citric acid and water,in which the concentration of citric acid is lower than the previouscharge (a2).

In general, the volume to mass ratio of water to citric acid in the lowcitric acid mixture may range from about 10:1 to about 22:1. In variousembodiments, the volume to mass ratio of water to citric acid in the lowcitric acid mixture may range from about 10:1 to about 22:1, from about12:1 to about 20:1, or from about 14:1 to about 18:1. In someembodiments, the volume to mass ratio of water to citric acid may beabout 16.5:1. The second mixture of citric acid and water may be formedessentially as described above in section (II)(a)(i).

(v) Step E2

The next step of this iteration comprises forming a second mixture ofsufentanil citrate (low citric acid) by adding about 65% to about 96% ofthe total amount of sufentanil base to the low citric acid mixture of(d2). In general, the mole to mole ratio of citric acid to sufentanilbase may range from about 0.5:1 to about 3.0:1. In various embodiments,the mole ratio of citric acid to sufentanil base may range from about0.5:1 to 3.0:1, from about 0.75:1 to 2.0:1, or from about 0.9:1 to about1.1:1. In exemplary embodiments, the mole to mole ratio of citric acidto sufentanil base may be about 1.0:1. In various embodiments, theamount of sufentanil base added to the mixture of (d2) may be range fromabout 65% to about 70%, from about 70% to about 75%, from about 75% toabout 80%, from about 80% to about 85%, from about 85% to about 90%,from about 90% to about 96% of total amount of sufentanil base used inthe process. In exemplary embodiments, the amount of sufentanil basesadded to the mixture of (d2) may range from about 80% to about 90%, orabout 85%, of the total amount of sufentanil base.

In general, step (e2) is conducted at a temperature of at least about90° C. For example, the step may be conducted at a temperature rangingfrom about 90° C. to about 95° C., from about 95° C. to about 100° C.,or greater than about 100° C.

Contact between sufentanil base and the low citric acid mixture at step(e2) may proceed for about 0.5 hours to about 24 hours. In someembodiments, the reaction may proceed from about 0.5 hours to about 1hour, from about 1 hour to about 3 hours, from about 3 hours to about 4hours, from about 4 hours to about 6 hours, from about 6 hours to about8 hours, from about 8 hours to about 12 hours, from about 12 hours toabout 18 hours, or from about 18 hours to about 24 hours. Contactbetween sufentanil base and citric acid may be facilitated by stirring,mixing, shaking, or any other means known in the art.

The reaction may be conducted in an inert atmosphere (e.g., undernitrogen or argon) and under ambient pressure. In various embodiments,the mixture of (e2) may be substantially or completely free of an oilphase comprising a sufentanil species. In some embodiments, the mixtureof (e2) may be filtered (polishing filtration) to remove undissolvedsufentanil base and/or other impurities before proceeding to the nextstep.

(vi) Step F2

The second iteration further comprises (f2) adding the (hot) secondmixture of sufentanil citrate (low citric acid) from step (e2) to thefirst mixture of sufentanil citrate (high citric acid) from step (c2).In general, the first mixture of sufentanil citrate is kept at atemperature that ranges from about 5° C. to about 30° C. while thesecond mixture is added to the first mixture. In some embodiments, thetemperature of the first mixture may range from about 5° C. to about 10°C., from about 10 to about 20° C., or from about 20 ° C. to about 30° C.In exemplary embodiment, the temperature of the first mixture is kept atabout 10° C. to about 23° C. during addition of the second mixture.

The addition of the second mixture to the first mixture may occur over aperiod of about 0.5 hour to about 4 hours. In various embodiments, theduration of the addition may range from about 0.5 to about 1 hour, fromabout 1 hour to about 2 hours, or from about 2 hours to about 3 hours.In exemplary embodiments, the duration of the addition may be about twohours. The first mixture may be stirred or mixed during the addition ofthe second mixture.

(vii) Step G2

The next step of the iteration comprises cooling the mixture of (f2) toform solid sufentanil citrate. The cooling step may be conductedessentially as described above in section (II)(a)(iii).

(viii) Step H2

This iteration may further comprise (h2) recovering the solid sufentanilcitrate from the mixture of (g2), essentially as detailed above insection (II)(a)(iv). The mixture remaining after the recovery of thesolid sufentanil citrate at step (h2) may be further processed accordingto section (III) below to provide solid sufentanil base.

(III) Process for Forming Sufentanil Base from Sufentanil Citrate inSolvent

Another aspect of the present disclosure provides a process for formingsufentanil base from sufentanil citrate. The process comprises (a)contacting sufentanil citrate with at least one polar solvent to form amixture; and (b) contacting the mixture with a proton acceptor (a base),thereby forming sufentanil base. The process may further comprise (c)optionally cooling the mixture from step (b) to form solid sufentanilbase; and (d) recovering solid sufentanil base.

In various embodiments, step (a) of the process for forming sufentanilbase from sufentanil citrate is omitted and the process is conductedusing a mixture remaining after recovery of solid sufentanil citrateduring any of the processes detailed in sections (I) or (II) above. Inparticular, refer to sections (I)(g), (II)(a)(iv), and (II)(b)(viii).

(a) Step A—Reaction Mixture

Step (a) of the process comprises contacting sufentanil citrate with atleast one polar solvent to form a mixture. The process commences withthe formation of a mixture comprising sufentanil citrate and at leastone polar solvent. The at least one polar solvent may be any polarnon-aqueous solvent described above at section (I)(a), water, orcombinations thereof. In various embodiments, the at least one polarsolvent may be selected from the group consisting of ethyl acetate,isopropyl acetate, methyl isobutyl ketone, methyl ethyl ketone, C₁-C₅alcohol, or water. In some exemplary embodiments, the at least one polarsolvent may be 2-propanol. In other exemplary embodiments, the at leastone polar solvent may be water. In still other exemplary embodiments,the polar solvent comprises ethanol and water.

In general, the volume to mass ratio of the solvent to sufentanilcitrate ranges from about 0.5:1 to about 200:1. In various embodiments,the volume to mass ratio of the solvent to sufentanil citrate may rangefrom about 0.5:1 to 200:1, from about 1.25:1 to 150:1, from about 2.5:1to 100:1, or from about 3.75:1 to about 50:1. In exemplary embodiments,the volume to mass ratio of the solvent to sufentanil citrate may rangefrom about 5:1 to about 25:1.

(b) Step A—Reaction Condtiions

In general, contact between the polar solvent and sufentanil citrate isconducted at a temperature that ranges from about 20° C. to about 90° C.In various embodiments, the temperature may range from about 20° C. toabout 30° C., from about 30° C. to about 40° C., from about 40° C. toabout 50° C., from about 50° C. to about 60° C., from about 60° C. toabout 70° C., from about 70° C. to about 80° C., or from about 80° C. toabout 90° C. Typically, contact between the polar solvent and sufentanilcitrate is allowed to proceed for a sufficient period of time until ahomogenous mixture forms. The duration of contact may range from aboutseveral minutes to several hours.

In some embodiments, the mixture may be filtered (polishing filtration)before proceeding to the next step. In particular, the mixture may befiltered at a temperature that ranges from about 20° C. to about 90° C.,as described above, in order to remove, for example, undissolvedsufentanil citrate or other impurities before proceeding to reactionwith a proton acceptor.

(c) Step B—Reaction Mixture

Step (b) of the process further comprises contacting the mixture fromstep (a) with a proton acceptor, thereby forming sufentanil base. Ingeneral, the pKa of suitable proton acceptors ranges from about 7 toabout 13. The proton acceptor may be organic or inorganic.Representative inorganic salts include, but are not limited to, boratesalts (such as, for example, Na₃BO₃), di- and tri-basic phosphate salts(such as, for example, Na₂HPO₄ and Na₃PO₄), bicarbonate salts (such as,for example, NaHCO₃, KHCO₃, mixtures thereof, and the like), hydroxidesalts (such as, for example, NaOH, KOH, mixtures thereof, and the like),carbonate salts (such as, for example, Na₂CO₃, K₂CO₃, mixtures thereof,and the like), and combinations of any of the foregoing. In exemplaryembodiments, the proton acceptor comprises a hydroxide. In particularembodiments, the proton acceptor may be potassium hydroxide, sodiumhydroxide, or combinations thereof.

The mole to mole ratio of sufentanil citrate to the proton acceptor mayrange from about 1:1.0 to about 1:6.0. In some embodiments, the mole tomole ratio of sufentanil citrate to the proton acceptor may range fromabout 1:1.0 to 1:6.0, from about 1:1.1 to about 1:5.0, from about 1:1.3to 1:4.0, or from about 1:1.5 to about 1:3.0. In some embodiments, themole to mole ratio of sufentanil citrate to the proton acceptor may befrom about 1:1.6 to about 1:2.0.

(d) Step B—Reaction Conditions

The temperature at which the reaction is conducted can and will vary. Ingeneral, the reaction is conducted at a temperature that ranges fromabout 20° C. to about 90° C. In various embodiments, the reaction may beconducted at a temperature from about 20° C. to about 30° C., from about30° C. to about 40° C., from about 40° C. to about 50° C., from about50° C. to about 60° C., from about 60° C. to about 70° C., from about70° C. to about 80° C., or from about 80° C. to about 90° C. Inexemplary embodiments, the reaction is conducted at a temperature ofabout 35° C. The reaction may be conducted in an inert atmosphere (e.g.,under nitrogen or argon) and under ambient pressure.

Typically, the reaction is allowed to proceed for a sufficient period oftime until the reaction is complete. In a completed reaction, the amountof sufentanil citrate remaining in the reaction mixture may be less thanabout 3%, or less than about 1%. In general, the reaction may proceedfor about 0.5 hours to about 24 hours. In some embodiments, the reactionmay proceed from about 0.5 hours to about 1 hour, from about 1 hour toabout 3 hours, from about 3 hours to about 4 hours, from about 4 hoursto about 6 hours, from about 6 hours to about 8 hours, from about 8hours to about 12 hours, from about 12 hours to about 18 hours, or fromabout 18 hours to about 24 hours.

The sufentanil base may be isolated from the reaction mixture usingtechniques known to those of skill in the art. Non-limiting examples ofsuitable techniques include precipitation, extraction, evaporation,distillation, chromatography, and crystallization. In exemplaryembodiments, the sufentanil base may be isolated according to themethods described in the sections (III)(e)-(f) below. The sufentanilbase may be used as is, or may be converted to another compound usingtechniques familiar to those of skill in the art.

The yield of sufentanil base can and will vary. Typically, the yield ofsufentanil base may be at least about 35%. In one embodiment, the yieldof sufentanil base may range from about 35% to about 65%. In anotherembodiment, the yield of sufentanil base may range from about 65% toabout 75%. In yet another embodiment, the yield of sufentanil base mayrange from about 75% to about 85%. In a further embodiment, the yield ofthe sufentanil base may range from about 85% to about 95%. In stillanother embodiment, the yield of the sufentanil base may be greater thanabout 95%.

(e) Step C

In some embodiments, step (c) of the process may further comprisecooling the mixture from step (b) to form solid sufentanil base.Generally, the reaction mixture of step (c) is the same as the reactionmixture of step (b), but in some embodiments, the reaction mixture ofstep (b) may be seeded with crystals of sufentanil base. In general, themole to mole ratio of sufentanil base seed crystals to sufentanil basein the mixture may range from about 0.0001:1 to about 0.05:1. In variousembodiments, the mole to mole ratio of sufentanil base seed crystals tosufentanil base in the mixture may range from about 0.0001:1 to 0.05:1,from about 0.00025:1 to 0.05:1, from about 0.0005:1 to 0.05:1, or fromabout 0.00075:1 to 0.05:1. In an exemplary embodiment, the mole to moleratio of sufentanil base seed crystals to sufentanil base in the mixturemay range from about 0.001:1 to about 0.05:1.

The temperature to which the mixture is cooled can and will vary. Ingeneral, the temperature may range from about −20° C. to about 60° C. Invarious embodiments, the temperature may range from about −20° C. toabout −10° C., from about −10° C. to about 0° C., from about 0° C. toabout 5° C., from about 5° C. to about 10° C., from about 10° C. toabout 20° C., from about 20° C. to about 30° C., from about 30° C. toabout 40° C., from about 40° C. to about 50° C., or from about 50° C. toabout 60° C. In exemplary embodiments, the temperature may range fromabout 0° C. to about 5° C.

Typically, step (c) is allowed to proceed for a sufficient period oftime until the reaction is complete, as detailed above. For example, thecooling step may proceed until no further (visible detectable) solidsufentanil base is formed. In general, the reaction may proceed forabout 0.5 hours to about 24 hours. In some embodiments, the reaction mayproceed from about 0.5 hours to about 1 hour, from about 1 hour to about3 hours, from about 3 hours to about 4 hours, from about 4 hours toabout 6 hours, from about 6 hours to about 8 hours, from about 8 hoursto about 12 hours, from about 12 hours to about 18 hours, or from about18 hours to about 24 hours.

(f) Step D

In some embodiments, the process further comprises step (d) whichcomprises recovering solid sufentanil base from the mixture of step (c).In particular, the solid sufentanil base may be recovered from thereaction mixture of step (c) through filtration, for example throughvacuum filtration. The solid sufentanil base may then be further driedusing any method known in the art to remove residual solvent. Suitablemethods include vacuum filtration, oven drying, and reduction in vacuo,for example on a rotary evaporator or attached to a high vacuummanifold. In further embodiments, the solid sufentanil base may be driedat elevated temperature, for example from about 35° C. to about 65° C.

In some embodiments, the solid sufentanil base may be contacted with anon-polar solvent to form crystalline sufentanil base. Representativenonpolar solvents include, but are not limited to, alkane andsubstituted alkane solvents (including cycloalkanes), aromatichydrocarbons, and combinations thereof. Specific nonpolar solvents thatmay be employed include, for example, benzene, chlorobenzene,chloroform, cyclohexane, dichloromethane, dichloroethane, fluorobenzene,heptane, hexanes, toluene, and combinations thereof. In exemplaryembodiments, the non-polar solvent may be an alkane, such as forexample, pentane, hexane, heptane, cyclopentane, cyclohexane,cycloheptane, or combinations thereof.

The yield of solid sufentanil base can and will vary. Typically, theyield of solid sufentanil base may be at least about 35%. In oneembodiment, the yield of solid sufentanil base may range from about 35%to about 65%. In another embodiment, the yield of solid sufentanil basemay range from about 65% to about 75%. In yet another embodiment, theyield of solid sufentanil base may range from about 75% to about 85%. Ina further embodiment, the yield of the solid sufentanil base may rangefrom about 85% to about 95%. In still another embodiment, the yield ofthe solid sufentanil base may be greater than about 95%. In an exemplaryembodiment, the solid sufentanil base recovered at step (d) may have ayield of at least about 90%.

In various embodiments, the solid sufentanil base recovered at step (d)may contain less than about 5000 ppm of solvent, for example, less thanabout 4500 ppm, less than about 4000 ppm, less than about 3500 ppm, lessthan about 3000 ppm, less than about 2500 ppm, less than about 2000 ppm,less than about 1500 ppm, less than about 1000 ppm, less than about 500ppm, or less than about 100 ppm.

Having described the invention in detail, it will be apparent thatmodifications and variations are possible without departing from thescope of the invention defined in the appended claims.

EXAMPLES

The following examples are included to demonstrate certain embodimentsof the invention. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples represent techniquesdiscovered by the inventors to function well in the practice of theinvention. Those of skill in the art should, however, in light of thepresent disclosure, appreciate that many changes can be made in thespecific embodiments that are disclosed and still obtain a like orsimilar result without departing from the spirit and scope of theinvention, therefore all matter set forth is to be interpreted asillustrative and not in a limiting sense.

Example 1 Sufentanil Citrate (IPA+Anhydrous Citric Acid)—Method A

Sufentanil base (1.09 g, 2.81 mmol) was stirred and heated todissolution (about 35° C.) in 2-propanol (8 mL). Anhydrous citric acid(0.56 g, 2.91 mmol, 1.04 eq.) was added and the mixture further heatedto 40° C. to ensure dissolution. The mixture was sterile filteredthrough an appropriate filter. The reaction mixture was seeded withsufentanil citrate crystals (0.05 mol %) at 40° C. and held at thistemperature until crystallization occurred, thereby avoiding an oilphase. The reaction mixture was then cooled to <5° C. and held at thistemperature for about 2 hours. The solids were filtered on a Büchnerfunnnel and washed with 1 mL cold (<5° C.) 2-propanol. After drying in aconvection oven at 58-62° C., the product was a white powder (1.47 g,90.7%). The product typically assayed at 99.29 wt. % with 4600 ppmresidual 2-propanol.

Example 2 Sufentanil Citrate (IPA+Anhydrous Citric Acid)—Method B

Sufentanil base (130.71 g, 338.14 mmol) was stirred and heated todissolution to a temperature of about 72° C. in 2-propanol (378 mL).Anhydrous citric acid (65.66 g, 341.74 mmol) was dissolved in 2-propanol(351.5 mL) and added to the 2-propanol sufentanil base solution withstirring over a period of about 50 minutes. The temperature of thereaction mixture was maintained above at least 62° C. during theaddition, then heated to 75° C. and sterile filtered. The reaction wascooled to about 62° C. and seeded with sufentanil citrate (220 mg, 0.38mmol, 0.001 mol %). The reaction mixture was maintained for 4 hours at60° C. and then allowed to cool to ambient temperature (about 25° C.)and maintained at ambient temperature for 16 hours with stirring, andthen cooled to between about 0° C. and about 5° C. with stirring forabout 30 minutes. The reaction mixture containing solid sufentanilcitrate was filtered on a Büchner funnel and washed with cold (<5° C.)2-propanol (125 mL). This procedure yielded white crystals (190.42 g,97.3%), after vacuum air drying for 3 days on the Bühner funnel. Theassay indicated that the material contained between 99 and 101 wt. %sufentanil citrate with <5000 ppm residual 2-propanol.

Example 3 Sufentanil Citrate (IPA+Citric Acid Monohydrate)—Method A

Sufentanil base (1.02 g, 2.63 mmol) was stirred and heated todissolution (about 35° C.) in 2-propanol (8 mL). Citric acid monohydrate(0.58 g, 2.76 mmol, 1.05 eq.) was added and the mixture further heatedto 40° C. to ensure dissolution. The mixture was sterile filteredthrough an appropriate filter. The reaction mixture was seeded withsufentanil citrate crystals (0.05 mol %) at 40° C. and held at thistemperature until crystallization occurred, thereby avoiding an oilphase. The reaction mixture was then cooled to <5° C. held at thistemperature for about 2 hours. The solids were filtered on a Büchnerfunnel and washed with 1 mL cold (<5° C.) 2-propanol. After drying in aconvection oven at 58-62° C., the product was a white powder (1.43 g,93.7%). The product typically assayed at 100.28 wt. % with 4800 ppmresidual 2-propanol.

Example 4 Sufentanil Citrate (IPA+Citric Acid Monohydrate)—Method B

Sufentanil base (1.02 g, 2.63 mmol) was charged to a 25 mL three-neckedflask with 2-propanol (4 mL) and stirred with a magnetic stirrer. Themixture was heated to 51° C. to dissolve all the sufentanil. Citric acidmonohydrate (0.59 g, 2.81 mmol, 1.07 eq.) was charged to a separateflask with 2-propanol (3.9 mL) and stirred to dissolve at ambienttemperature, about 22° C. The citric acid solution was added to thesufentanil solution and stirred; the temperature of the combinedsolution was 39° C. The solution was allowed to cool to ambienttemperature while stirring continued; after about 30 minutes thesolution became cloudy and the sufentanil citrate slowly came out ofsolution. The product suspension was cooled in an ice bath for 2 hours(0-5° C.), filtered, and air dried for 2 hours to give sufentanilcitrate as a white crystalline solid (1.34 g, 88.2%).

Example 5 Sufentanil Citrate (2-Propanol+Citric Acid Monohydrate)—MethodA with Finer Control on Residual 2-Propanol Levels

Sufentanil base (13.00 g, 33.63 mmol) and citric acid monohydrate (7.21g, 34.31 mmol, 1.02 eq) were added to a 250 mL flask equipped with amechanical stirrer under nitrogen. 2-Propanol (57 mL) was charged to theflask and the slurry was stirred to mix the contents and then heated todissolve at 80° C. The hot solution was filtered through a 0.45 μmfilter and the flask and filter were rinsed with 2-propanol (9 mL). Theclear hot solution was cooled to 60° C. and seeded with sufentanilcitrate (20 mg, 0.034 mmol, 0.10 mol %). The cloudy solution was cooledover 1-2 hours to 50° C. and held for 18 hrs. The white slurry wasfiltered at 50° C. on a Büchner funnel and the solids were washed with13.0 mL of 2-propanol. The isolated solid was dried at 60° C. to aconstant weight in a convection oven. This gave the product as a whitepowder (17.85 g, 91.7%), 99.86 wt. % assay, with typically 1041 ppm ofresidual 2-propanol.

Example 6 Sufentanil Citrate (1-Butanol+Citric Acid Monohydrate)

Sufentanil base (1.01 g, 2.61 mmol) was stirred and dissolved 1-butanol(8 mL) at room temperature (about 23° C.). Citric acid monohydrate (0.58g, 2.76 mmol, 1.06 eq.) was added. The mixture was sterile filteredthrough an appropriate filter, and the mixture was stirred overnight.The suspension was cooled to <5° C., held for 2 hours and the solidswere filtered on a Büchner funnel and washed with 2 mL cold (<5° C.)1-butanol. After drying in a convection oven at 55-65° C., the productwas a white powder (1.44 g, 95.4%). The product typically assayed at95.69 wt. %.

Example 7 Sufentanil Citrate (2-Butanol+Citric Acid Monohydrate)

Sufentanil base (1.05 g, 2.72 mmol) was stirred in 2-butanol (8 mL) atroom temperature. The mixture was heated at 30° C. for 30 minutes toobtain dissolution, filtered and then allowed to cool to roomtemperature. Citric acid monohydrate (0.60 g, 2.85 mmol, 1.00 eq.) wasadded and the mixture stirred to ensure dissolution. After about 1 hourat room temperature, crystallization took place. The suspension wasstirred overnight, then cooled to <5° C., held for 2 hours and thesolids were filtered on a Büchner funnel and washed with 2 mL cold (<5°C.) 2-butanol. After drying in a convection oven at 55-65° C., theproduct was a white powder (1.43 g, 91.2%). The product typicallyassayed at 99.85 wt %.

Example 8 Sufentanil Citrate (Ethyl Acetate+Citric Acid Monohydrate)

Sufentanil base (1.04 g, 2.69 mmol) was stirred and heated todissolution (about 30° C.) in ethyl acetate (8 mL). Citric acidmonohydrate (0.62 g, 2.95 mmol, 1.10 eq.) was added and the mixturefurther heated to from about 76° C. to about 78° C., and held for 1hour. The suspension was cooled to <5° C. and held for about 0.5 hours.The solids were filtered on a Büchner funnel and washed with 2 mL cold(<5° C.) ethyl acetate. After drying in a convection oven at 58-62° C.,the product was a white powder (1.46 g, 93.6%). Product typicallyassayed at 98.79 wt % with 3100 ppm residual ethyl acetate.

Example 9 Sufentanil Citrate (Isopropyl Acetate+Citric Acid Monohydrate)

Sufentanil base (1.01 g, 2.61 mmol) was stirred and heated todissolution (about 30° C.) in isopropyl acetate (8 mL). Citric acidmonohydrate (0.57 g, 2.71 mmol, 1.04 eq.) was added and the mixturefurther heated to about 80° C. and held for 1 hour. The suspension wascooled to <5° C. and held for about 0.5 hours. The solids were filteredon a Büchner funnel and washed with 2 mL of cold (<5° C.) isopropylacetate. After drying in a convection oven at 45-54° C., the product asa white powder (1.27 g, 84.1%). The product typically assayed at 99.54wt %.

Example 10 Sufentanil Citrate (Methyl Isobutyl Ketone+Citric AcidMonohydrate)

Sufentanil base (1.06 g, 2.74 mmol) was stirred and heated todissolution (about 30° C.) in methyl isobutyl ketone (8 mL). Citric acidmonohydrate (0.61 g, 2.90 mmol, 1.06 eq.) was added. The reactionmixture was filtered if required and then stirred at room temperatureovernight. The suspension was cooled to <5° C. and held for about 0.5hours. The solids were filtered on a Büchner funnel and washed with 2 mLcold (<5° C.) methyl isobutyl ketone. After drying in a convection ovenat 55-65° C., the product was a white powder (1.34 g, 84.3%). Theproduct typically assayed at 93.67 wt %.

Example 11 Sufentanil Citrate (Methyl Ethyl Ketone+Citric AcidMonohydrate)

Sufentanil base (1.01 g, 2.61 mmol) was stirred and dissolved methylethyl ketone (8 mL) at room temperature. Citric acid monohydrate (0.57g, 2.71 mmol) was added, crystallization was observed after 5 minutesand the mixture stirred at room temperature overnight. The suspensionwas cooled to <5° C. and held for about 0.5 hours. The solids werefiltered on a Büchner funnel and washed with 2 mL cold (<5° C.) methylethyl ketone. After drying in a convection oven at 55-65° C., theproduct was a white powder (1.47 g, 97.4%). The product typicallyassayed at 96.27 wt %.

Example 12 Sufentanil Citrate (25% v/v Methanol in Water+Citric AcidMonohydrate)

Sufentanil base (0.97 g, 2.51 mmol) was stirred and heated todissolution (about 55° C.) in 25% v/v methanol in water (8 mL). Citricacid monohydrate (0.55 g, 2.62 mmol, 1.04 eq.) was added and the mixturecooled. The reaction was cooled to room temperature (crystallizationoccurred at 35.0° C.). The suspension was stirred overnight. Thereaction was then cooled to <5° C., held for 2 hours, then filtered on aBüchner funnel and washed with 2 mL cold (<5° C.) 25% v/v methanol inwater. After drying in a convection oven at 55-65° C., the product waswhite plates (1.20 g, 82.8%). The product typically assayed at 100.26 wt%.

Example 13 Sufentanil Citrate—Water Method 1

Citric acid anhydrous (4.32 g, 22.48 mmol) was dissolved in de-ionizedwater (30 mL). To this was added sufentanil base (3.00 g, 7.76 mmol,0.34 eq) and then mixed to dissolution at 75-85° C. The mixture wasfiltered then cooled to room temperature, the product crystallizedthereafter within 3 hours. The mixture was then cooled to 0-5° C. andheld for 1-3 hours. The mixture was filtered on a Büchner funnel andwashed with water (4 mL). The wet cake was dried in a vacuum oven (˜200mbar, 55-60° C. with a nitrogen sweep for 16 hours. This gave theproduct as a white powder (3.60 g, 80.2%), with 99.09 wt. % assay.

Example 14 Sufentanil Citrate—Water Method 2

In Reactor 1, citric acid anhydrous (10.46 g, 54.44 mmol, 2.81 eq.) wasdissolved in deionized water (53 mL). Sufentanil base (7.50 g, 19.40mmol) was charged and the reaction placed under nitrogen, heated untilall the solids dissolved (75-80° C.), and filtered. The filter wasrinsed forward with deionized water (7.0 mL). The reaction was stirredand allowed to cool to ambient temperature (about 23° C.). The systemwas heated to 76.9° C. to redissolve the solids; the temperature wasreduced then to 42-44° C., which resulted in the solution becomingcloudy within 1.2 hours and a thick slurry of crystalline sufentanilcitrate developed within 1.8 hours. No stickiness or gumminess wasobserved under these conditions. The sufentanil citrate/water slurry wascooled and held at about 14° C.

In Reactor 2, citric acid anhydrous (21.37 g, 111.2 mmol, 1.01 eq.) wasdissolved in de-ionized water (350 mL). Sufentanil base (42.52 g, 110.0mmol) was added, the mixture was placed under nitrogen, heated andstirred to dissolve the solids (95-98° C.), and filtered. The filter wasrinsed forward with 50 mL of deionized water into the batch. The hotsufentanil citrate solution (the contents of Reactor 2) was added over aperiod of about 1 hour to the cooled aqueous sufentanil citrate slurry(Reactor 1) with vigorous stirring, such that the temperature wasmaintained between 17.5° C. and 18.5° C. After the addition wascomplete, the reaction mixture was stirred at ambient temperatureovernight and then cooled to 2.7° C. for 1 hour. The sufentanil citratewas recovered by filtration, washed with cold deionized water (50 mL),air-dried for 16 hours, then dried in a vacuum oven (100-200 mbar,56-62° C. with a nitrogen sweep) for 16 hours. This procedure gavesufentanil citrate as a white powder (66.19 g, 88.4%). The motherliquors were reserved for recovery of the sufentanil base.

Example 15 Sufentanil Base (from Sufentanil Citrate Mother Liquors)

The combined mother liquor and aqueous cake washes from the preparationof sufentanil citrate (Example 12, about 460 mL) were pH-adjusted from2.83 in steps to 5.03 and 6.04 with 50% w/w aqueous sodium hydroxide.After 0.5 hours at a pH of about 6, the solution became cloudy, a moredilute solution of base (15% w/w) was used to adjust the pH to 7.37 andthen to 12.11. The suspension was cooled on an ice bath to 2.6° C. forapproximately 1 hour and the sufentanil base was recovered byfiltration. The sufentanil base was air-dried for 16 hours and dried ina vacuum oven (100-200 mbar, 56-62 ° C. with a nitrogen sweep) for 16hours. This procedure gave recovered sufentanil base as a white powder(4.97 g, 9.9% recovery based on 50.02 g of total sufentanil base chargedin Example 12).

Example 16 Sufentanil Base (from Sufentanil Citrate)

Sufentanil citrate (65.40 g, 113.0 mmol) was mixed with ethanol (128 mL)and deionized water (200 mL), and then heated to dissolution (about 35°C.). The pH of this solution was adjusted to >12.5 by the addition of50% w/w aqueous sodium hydroxide, and then cooled to <5° C. in an icebath. The product was filtered and washed with cold deionized water(about 20 mL). The crude sufentanil base was air-dried then dissolved inn-heptane (146 mL) at about 75° C., with any residual water removedusing a Dean-Stark trap. The hot n-heptane solution was passed through abed of decolorizing carbon (Darco™, 2.00 g) supported on bleacheddiatomaceous earth (Celite™, 2.00 g) and allowed to cool roomtemperature followed by cooling to 0-5° C. The sufentanil base wasobtained by filtration of the white prisms on a Büchner funnel followedby washing with 2 mL cold (<5° C.) n-heptane. After air-drying,sufentanil base was white needles (43.46 g, 99.5%). The producttypically assayed at 100.40 wt. %.

What is claimed is:
 1. A process for preparing sufentanil citrate fromsufentanil base, the process comprising: (a) forming a reaction mixturecomprising sufentanil base, citric acid, and isopropyl alcohol; (b)heating the reaction mixture to a temperature of 70° C. to 90° C. toform a solution comprising sufentanil citrate; (c) cooling the solutioncomprising sufentanil citrate to 50° C. to 70° C., seeding with crystalsof sufentanil citrate, and maintaining the temperature at 50° C. to 60°C. thereby forming a slurry, the slurry comprising solid sufentanilcitrate; and (d) maintaining the temperature of the slurry at 50° C. to60° C. and filtering the slurry at 50° C. to 60° C. to recover the solidsufentanil citrate, which contains less than about 2000 ppm of isopropylalcohol.
 2. The process of claim 1, further comprising: (e) contactingthe mixture remaining after recovery of solid sufentanil citrate with aproton acceptor to form a sufentanil base mixture; (f) cooling thesufentanil base mixture to form solid sufentanil base; and (g)recovering solid sufentanil base.
 3. The process of claim 2, furthercomprising contacting solid sufentanil base from step (g) with anon-polar solvent to form a mixture, heating the mixture to dissolve thesufentanil base, and cooling the mixture to form crystalline sufentanilbase.
 4. The process of claim 3, wherein the proton acceptor comprises ahydroxide and the non-polar solvent is an alkane.